1. Field of the Invention The present invention relates to a process for increasing bone mass in a human afflicted with osteoporosis.
2. Description of the Prior Art
Osteoporosis is a generic description for a group of diverse diseases which are characterized by a reduction in the mass of bone per unit volume with a histologically normal ratio of osteoid to bone. The effects of these diseases are particularly severe when the mass per unit volume decreases to a level below that required for adequate mechanical support. Osteoporosis is a particularly important cause of morbidity in the elderly. The most frequent symptoms are back pain and deformity of the spine resulting from a collapse of the vertebrae, especially in the lumbar and thoracic spine regions.
The problem presented worldwide by osteoporosis is truly staggering. It is estimated that in the United States alone, there are millions who symptomatically exhibit this disease. The disease appears to be an invariable accompaniment of aging, particularly among women, and the incidence is increasing with the age expectancy of the population. Osteoporosis often occurs when there is malnutrition, as a complication due to immobilization and paralysis, as a result of liver, kidney, or intestinal disease, and also after or during various forms of endocrine or rheumatic diseases. As improved public health measures increase life expectancy in third world nations and underdeveloped countries, the incidence of osteoporosis is beginning to be recognized as a significant problem in these countries as well. For these reasons, a treatment that can arrest the course of this widely present, destructive disease represents a significant medical advance.
Various methods have been discussed in the prior art for increasing bone mass in humans with osteoporosis. These treatments include administration of sodium fluoride, androgens, biologically active forms of parathyroid hormone alone, calcitonin, and calcitonin in combination with high dietary phosphate. Except for treatment with sodium fluoride, the effects of these treatments are modest. Sodium fluoride treatment increases trabecular bone in some patients but has uncertain effects on total bone mass and bone strength, a high risk of osteomalacia, as well as other unpleasant side effects.
In addition to these methods of treating osteoporosis by increasing bone mass, other methods are known which are designed to preserve existing bone mass. These methods involve the use of estrogens or calcium alone, or 1-hydroxy vitamin D.sub.3 or 1,25-dihydroxy vitamin D.sub.3 alone.
Typical publications disclosing and discussing these prior art methods include the following. Brugger et al., U.S. Pat. No. 3,956,260, discloses the preparation and use of a synthetic polypeptide for the treatment of osteoporosis This polypeptide is unrelated to that of the present invention. Christie et al., U.S. Pat. No. 4,241,051, teaches topical application of the hormone calcitonin for the treatment of diseased bone in the ear.
Reeve et al., British Medical Journal, 280:1340 (1980), describes the results of a multicenter trial evaluating the effect of a fragment of human parathyroid hormone (hPTH (1-34)) on osteoporosis in humans. The authors report that this regimen resulted in a considerable increase in axial trabecular bone, but calcium retention, and hence, total bone mass, improved in only about half of these patients. In other patients calcium retention worsened and therefore, total bone mass decreased. The authors speculate that hPTH (1-34) might be most effective if administered in combination with estrogen, calcitonin, a diphosphonate, or some other agent that would limit resorption while allowing bone formation to continue.
Reeve et al., in Monoclonal Antibodies And Developments In Immunoassay, p. 239, published by Elsevier/North-Holland Biomedical Press (1981), report their progress towards answering some of the questions raised in the above study. The authors state that their studies of intestinal calcium absorption point to a possible defect in osteoporosis and further speculate that it may be necessary to circumvent this defect with, for example, 1,25-(OH).sub.2 vitamin D.sub.3 in modest dosage, given during intervals when no hPTH injection is administered.
Hefti et al., Clinical Science, 62:389 (1982), describes studies using a high calcium diet supplemented with either parathyroid hormone or 1,25-(OH)2 vitamin D3 using normal and osteoporotic adult rats. The authors report that, although these studies showed an increase of whole-body calcium and skeletal mass, there was no restoration of individual trabeculae lost during the development of osteoporosis. Endo et al., Nature, 286:262 (1980), discuss the use of metabolites of vitamin D in conjunction with parathyroid hormone (PTH) to stimulate bone formation in vitro. However, these treatments with PTH and 1,25(OH).sub.2 vitamin vitamin D.sub.3 were no more effective than PTH alone in stimulating re-calcification of bone.
Rader et al., Calcified Tissue International, 29(1):21 (1979), describes the treatment of thyroparathyroidectomized rats with dietary calcium and intraperitoneal injection of a parathyroid extract. Although this treatment stimulated 1,25-(OH).sub.2 vitamin D.sub.3 production and effected a marked increase in bone mineralization, it was also found to produce bone resorption as evidenced by the appearance of cavities in the cortical bone. There was no effect on rates of bone formation, or bone matrix apposition. Wong et al., Surgical Forum, 30:100 (1979), teach the administration to thyroparathyroidectomized dogs of daily intramuscular parathyroid extract or oral 1,25-(OH).sub.2 vitamin D.sub.3 simultaneously with thyroid replacement therapy. The effect of these treatments on absorption of dietary calcium is discussed in the context of parathyroidism although not in the context of osteoporosis.
Peacock et al., Vitamin D Proceedings Workshop., E. Norman, Ed., p. 411 (1977), disclose the inhibition by calcitonin and steroid sex hormones of the resorptive effect of vitamin D metabolites and parathyroid hormone on mouse calvaria bone in tissue culture. Pechet et al., American Journal of Medicine, 43(5):696 (1967), teach that minimum levels of parathyroid hormone are necessary in order for vitamin D to exert its effects on bone resorption rather than bone formation. In Mahgoub et al., Biochemical and Biophysical Research Communications, 62:901 (1975), the authors describe experiments and state that active vitamin D metabolites (25-0H vitamin D.sub.3 and 1,25-(OH).sub.2 vitamin D.sub.3) potentiate the ability of parathyroid hormone to elevate the cyclic AMP levels of cultured rat fetal bone cells.
None of these methods, however, have provided a clinically useful technique for treating osteoporosis and related disorders and often cause undesirable side effects. As a consequence, there is still a need for a generally effective treatment having minimal side effects.